title: USP18 inhibits NF-κB and NFAT activation during Th17 differentiation by deubiquitinating the TAK1-TAB1 complex.
abstract: Reversible ubiquitin modification of cell signaling molecules has emerged as a critical mechanism by which cells respond to extracellular stimuli. Although ubiquitination of TGF-β-activated kinase 1 (TAK1) is critical for NF-κB activation in T cells, the regulation of its deubiquitination is unclear. We show that USP18, which was previously reported to be important in regulating type I interferon signaling in innate immunity, regulates T cell activation and T helper 17 (Th17) cell differentiation by deubiquitinating the TAK1-TAB1 complex. USP18-deficient T cells are defective in Th17 differentiation and Usp18(-/-) mice are resistant to experimental autoimmune encephalomyelitis (EAE). In response to T cell receptor engagement, USP18-deficient T cells exhibit hyperactivation of NF-κB and NFAT and produce increased levels of IL-2 compared with the wild-type controls. Importantly, USP18 is associated with and deubiquitinates the TAK1-TAB1 complex, thereby restricting expression of IL-2. Our findings thus demonstrate a previously uncharacterized negative regulation of TAK1 activity during Th17 differentiation, suggesting that USP18 may be targeted to treat autoimmune diseases.
authors.affiliation: Department of Immunology, Center for Inflammation and Cancer, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xikui
authors.initials: X
authors.lastname: Liu
authors.forename: Hongxiu
authors.initials: H
authors.lastname: Li
authors.forename: Bo
authors.initials: B
authors.lastname: Zhong
authors.forename: Marzenna
authors.initials: M
authors.lastname: Blonska
authors.forename: Sara
authors.initials: S
authors.lastname: Gorjestani
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.forename: Qiang
authors.initials: Q
authors.lastname: Tian
authors.forename: Dong-Er
authors.initials: DE
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism; D002384:Catalysis; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D055786:Gene Knockout Techniques; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase; D054875:Ubiquitination; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010450:Endopeptidases; D007376:Interleukin-2; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D011948:Receptors, Antigen, T-Cell; D043222:Ubiquitin Thiolesterase; D000099151:MAP Kinase Kinase Kinase 7; C531463:Tab1 protein, mouse; C118306:Usp18 protein, mouse